Therapeutic agents may be delivered to a targeted location in a human utilizing a number of different methods. For example, agents may be delivered nasally, transdermally, intravenously, orally, or via other conventional methods. Delivery may vary by release rate (i.e., quick release or slow release). Delivery may also vary as to how the drug is administered. Specifically, a drug may be administered locally to a targeted area, or administered systemically.
With systemic administration, the therapeutic agent is administered in one of a number of different ways including orally, inhallationally, or intravenously to be systemically processed by the patient. However, there are drawbacks to systemic delivery of a therapeutic agent, one of which is that high concentrations of the therapeutic agent travels to all portions of the patient's body and can have undesired effects at areas not targeted for treatment by the therapeutic agent. Furthermore, large doses of the therapeutic agent only amplify the undesired effects at non-target areas. As a result, the amount of therapeutic agent that results in application to a specific targeted location in a patient may have to be reduced when administered systemically to reduce complications from toxicity resulting from a higher dosage of the therapeutic agent.
An alternative to the systemic administration of a therapeutic agent is the use of a targeted local therapeutic agent delivery approach. With local delivery of a therapeutic agent, the therapeutic agent is administered using a medical device or apparatus, directly by hand, or sprayed on the tissue, at a selected targeted tissue location of the patient that requires treatment. The therapeutic agent emits, or is otherwise delivered, from the medical device apparatus, and/or carrier, and is applied to the targeted tissue location. The local delivery of a therapeutic agent enables a more concentrated and higher quantity of therapeutic agent to be delivered directly at the targeted tissue location, without having broader systemic side effects. With local delivery, the therapeutic agent that escapes the targeted tissue location dilutes as it travels to the remainder of the patient's body, substantially reducing or eliminating systemic side effects.
Local delivery is often carried out using a medical device as the delivery vehicle. One example of a medical device that is used as a delivery vehicle is a stent. Boston Scientific Corporation sells the Taxus® stent, which contains a polymeric coating for delivering Paclitaxel. Johnson & Johnson, Inc. sells the Cypher® stent which includes a polymeric coating for delivery of Sirolimus.
Targeted local therapeutic agent delivery using a medical device can be further broken into two categories, namely, short term and long term. The short term delivery of a therapeutic agent occurs generally within a matter of seconds or minutes to a few days or weeks. The long term delivery of a therapeutic agent occurs generally within several weeks to a number of months. Typically, to achieve the long term delivery of a therapeutic agent, the therapeutic agent must be combined with a delivery agent, or otherwise formed with a physical impediment as a part of the medical device, to slow the release of the therapeutic agent.
U.S. patent Publication No. 2003/0204168 is directed to the local administration of drug combinations for the prevention and treatment of vascular disease. The publication discusses using intraluminal medical devices having drugs, agents, and/or compounds affixed thereto to treat and prevent disease and minimize biological reactions to the introduction of the medical device. The publication states that both bio-absorbable and biostable compositions have been reported as coatings for stents. They have been polymeric coatings that either encapsulate a pharmaceutical/therapeutic agent or drug, e.g. rapamycin, taxol etc., or bind such an agent to the surface, e.g. heparin-coated stents. These coatings are applied to the stent in a number of ways, including, though not limited to, dip, spray, or spin coating processes.
The publication goes on to state that although stents prevent at least a portion of the restenosis process, a combination of drugs, agents or compounds which prevents smooth muscle cell proliferation, reduces inflammation and reduces thrombosis or prevents smooth muscle cell proliferation by multiple mechanisms, reduces inflammation and reduces thrombosis combined with a stent may provide the most efficacious treatment for post-angioplasty restenosis. The systemic use of drugs, agents or compounds in combination with the local delivery of the same or different drug/drug combinations may also provide a beneficial treatment option.
The invention subsequently described in the '168 publication relates to the provision of polymeric coatings comprising a polyfluoro copolymer and implantable medical devices, for example, stents coated with a film of the polymeric coating in amounts effective to reduce thrombosis and/or restenosis when such stents are used in, for example, angioplasty procedures. Blends of polyfluoro copolymers are also used to control the release rate of different agents or to provide a desirable balance of coating properties, i.e. elasticity, toughness, etc., and drug delivery characteristics, for example, release profile. Polyfluoro copolymers with different solubilities in solvents may be used to build up different polymer layers that may be used to deliver different drugs or to control the release profile of a drug.
The coatings and drugs, agents or compounds described are described as being useful in combination with any number of medical devices, and in particular, with implantable medical devices such as stents and stent-grafts. Other devices such as vena cava filters and anastomosis devices may be used with coatings having drugs, agents, or compounds therein.
U.S. Pat. No. 6,358,556 is directed to a drug release stent coating. The patent describes processes for producing a relatively thin layer of biostable elastomeric material in which an amount of biologically active material is dispersed as a coating on the surfaces of a deployable stent. The coating is described as preferably being applied as a mixture, solution, or suspension of polymeric material and finely divided biologically active species dispersed in an organic vehicle or a solution or partial solution of such species in a solvent or vehicle for the polymer and/or biologically active species. Essentially the active material is dispersed in a carrier material that may be a polymer, a solvent, or both.
U.S. Pat. No. 6,299,604 is directed to a coated implantable medical device having a layer of bioactive material and a coated layer providing controlled release of the bioactive material. The patent discusses the idea that the degradation of an agent, a drug, or a bioactive material, applied to an implantable medical device may be avoided by covering the agent, drug, or bioactive material, with a porous layer of a biocompatible polymer that is applied without the use of solvents, catalysts, heat or other chemicals or techniques, which would otherwise be likely to degrade or damage the agent, drug or material. Those biocompatible polymers may be applied preferably by vapor deposition or plasma deposition, and may polymerize and cure merely upon condensation from the vapor phase, or may be photolytically polymerizable and are expected to be useful for this purpose. As such, this patent focuses on the use of polymers to act as drug delivery agents in providing a controlled release of a drug from an implanted medical device.
U.S. Publication No. 2003/0004564 is directed to a drug delivery platform. The publication describes compositions and methods for a stent based drug delivery system. The stent comprises a matrix, where the matrix has entrapped a pharmaceutical agent of interest. The matrix, for example microspheres, etc. resides within a channel formed on one or both of the abluminal or adluminal surfaces of the stent, and allows for release, usually sustained release, of the entrapped agent. The stent and matrix is encased with a gel covalently bound to the stent surface and optionally also covalently bound to the matrix, which prevents loss of the matrix during transport and implantation of the stent, and which affects the release of the biologically active agent, through degradation and diffusion characteristics. The matrix is described as a biodegradable, bioerodible, or biocompatible non-biodegradable matrix comprising a biologically active agent that is placed within the channels of the stent surface. The matrix may be of any geometry including fibers, sheets, films, microspheres, circular discs, plaques and the like. The gel is selected to be a polymeric compound that will fill the spaces between the matrix and the channel, that can be covalently bound to the stent surface and optionally covalently bound to the matrix, and that provides a porous protective barrier between the matrix and the environment, for example during storage, implantation, flow conditions, etc. The gel may contribute to the control of drug release through its characteristics of degradation and diffusion.
U.S. Pat. No. 4,952,419 is directed to a method of making antimicrobial coated implant devices. The reference discusses the desire to have better retention of coatings on the implant surface during mechanized implant packaging operations. The solution presented involves the use of a silicone fluid in contact with the surface of the implant and an antimicrobial agent in contact with the silicone fluid. There is no discussion of any therapeutic benefit inherent in the silicone fluid itself, and there is no suggestion that other oils can be utilized to control the delivery of the antimicrobial agent
The above-described references fail to teach or suggest the use of bio-absorbable fats or oils in any form as the drug delivery platform. In each instance, the drug delivery platform includes the use of a form of polymeric material, or silicone material, with a solvent additive. The polymeric material serves as either a base upon which a drug coating is applied, a substance mixed in with the drug to form the coating, or a top coating applied over a previously applied drug coating to control the release of the drug.
PCT application publication No. WO 00/62830 is directed to a system and method for coating medical devices using air suspension. The technique involves suspending a medical device in an air stream and introducing a coating material into the air stream such that the coating material is dispersed therein and coats the medical device. The publication discusses applying the coating to a number of different medical devices formed of a number of different materials. The publication further suggests that the coating materials can be comprised of therapeutic agents alone or in combination with solvents, and that the coating may provide for controlled release, which includes long-term or sustained release. As stated in the publication, a list of coating materials other than therapeutic agents include polymeric materials, sugars, waxes, and fats applied alone or in combination with therapeutic agents, and monomers that are cross-linked or polymerized. The publication goes on to discuss the use of a drug matrix formed of a polymer structure, which can be used to control the release rate of drugs combined with the polymer.
Although the '830 publication attempts to discuss every possible combination of delivery coating in combination with every drug or therapeutic agent that may have some utility in targeted delivery applications, there is no realization of the difficulty of using an oil for the controlled release of a therapeutic agent in a long term application. A list of potential delivery vehicles identifies waxes and fats, however there is no indication that such vehicles can be utilized for anything other than a short term drug delivery. A later discussion of controlled long term release of a drug mentions only the use of polymers to control the release.
U.S. Pat. No. 6,117,911 is directed to the use of compounds and different therapies for the prevention of vascular and non-vascular pathologies. The '911 patent discusses the possibility of using many different types of delivery methods for a therapeutic agent or agents to prevent various vascular and non-vascular pathologies. One such approach is described as providing a method of preventing or treating a mammal having, or at risk of developing, atherosclerosis, including administering an amount of a combination of aspirin or an aspirinate and at least one omega-3 fatty acid, wherein said amount of omega-3 fatty acid is effective to maintain or increase the level of TGF-beta so as to provide a synergistic effect with a therapeutic compound to inhibit or reduce vessel lumen diameter dimension. As such, the patent discusses some of the therapeutic benefits of primarily systemic administration of omega-3 fatty acids to affect TGF-beta levels when a therapeutic agent is combined with aspirin or aspirinate. That is, the dose or concentration of omega-3-fatty acid required to increase the level of TGF-beta is significantly greater, requiring long term systemic delivery.
PCT Application Publication No. WO 03/028622 is directed to a method of delivering drugs to a tissue using drug coated medical devices. The drug coated medical device is brought into contact with the target tissue or circulation and the drugs are quickly released onto the area surrounding the device in a short period of time after contact is made. The release of the drug may occur over a period of 30 seconds, 1 minute or 3 minutes. In one embodiment described in the publication, the carrier of the drug is a liposome. Other particles described as potential drug carriers include lipids, sugars, carbohydrates, proteins, and the like. The publication describes these carriers as having properties appropriate for a quick short term release of a drug combined with the carriers.
PCT application publication No. WO 02/100455 is directed to ozonated medical devices and methods of using ozone to prevent complications from indwelling medical devices. The application discusses having the ozone in gel or liquid form to coat the medical device. The ozone can be dissolved in olive oil, or other types of oil, to form a gel containing ozone bubbles, and the gel applied to the medical device as a coating. The application later asserts a preference for the gel or other coating formulation to be composed so that the ozone is released over time. However, there is no indication in the application as to how a slow controlled release of ozone can be affected. There is no enablement to a long term controlled release of ozone from the olive oil gel, however, there is mention of use of biocompatible polymers to form the coating that holds and releases the ozone. Other drugs are also suggested for combination with the ozone for delivery to a targeted location. The application later describes different application methods for the coating, including casting, spraying, painting, dipping, sponging, atomizing, smearing, impregnating, and spreading.
U.S. Pat. No. 5,509,899 is directed to a medical device having a lubricious coating. In the background section of this patent, it states that catheters have been rendered lubricious by coating them with a layer of silicone, glycerin, or olive oil in the past. It further states that such coatings are not necessarily satisfactory in all cases because they tend to run off and lose the initial lubricity rather rapidly and they can also lack abrasion resistance. Hydrophilic coatings have also been disclosed such as polyvinyl pyrrolidone with polyurethane interpolymers or hydrophilic polymer blends of thermoplastic polyurethane and polyvinyl pyrrolidone. Accordingly, the invention in the '899 patent is described as providing a biocompatible surface for a device which can impede blocking or sticking of two polymer surfaces when the surfaces are placed in tight intimate contact with each other such as is the case when the balloon is wrapped for storage or when a surface of one device will contact a surface of another device. The description goes on to describe numerous polymeric substances.
European Patent Application No. EP 1 273 314 is directed to a stent having a biologically and physiologically active substance loaded onto the stent in a stable manner. The biologically and physiologically active substance is gradually released over a prolonged period of time with no rapid short term release. In order to achieve the long term controlled release, the application describes placing a layer of the biologically and physiologically active substance on the surface of the stent, and placing a polymer layer on top of the biologically and physiologically active substance layer. The polymer layer acts to slow the release of the biologically and physiologically active substance. There is no discussion of an alternative to the polymer substance forming the polymer layer for controlling the release of the biologically and physiologically active substance. There are instances discussed when the biologically and physiologically active substance has insufficient adhesion characteristics to adhere to the stent. In such instances, the application describes using an additional substance mixed with the biologically and physiologically active substance to increase its adhesion properties. In the case of a fat soluble substance, the recommendation is the use of a low molecular weight fatty acid having a molecular weight of up to 1000, such as fish oil, vegetable oil, or a fat-soluble vitamin such as vitamin A or vitamin E. The application always requires use of the additional polymer coating to create the long term controlled release of the biologically and physiologically active substance.
A paper entitled “Evaluation of the Biocompatibility and Drug Delivery Capabilities of Biological Oil Based Stent Coatings”, by Shengqiao Li of the Katholieke Universiteit Leuven, discusses the use of biological oils as a coating for delivering drugs after being applied to stents. Three different coatings were discussed, a glue coating (cod liver oil mixed with 100% ethanol at a 1:1 ratio), a vitamin E coating (97% vitamin E oil solution mixed with 100% ethanol at a 1:1 ratio), and a glue+vitamin E coating (cod liver oil and 97% vitamin E oil solution mixed with 100% ethanol at a 1:1 ratio). Bare stents and polymer coated stents, along with stents having each of the above coatings, were implanted into test subjects, and analyzed over a four week period. At the end of the period, it was observed that the bare stents and polymer coated stents resulted in some minor inflammation of the tissue. The main finding of the study was that the glue coatings have a good biocompatibility with coronary arteries, and that the glue coating does not affect the degree of inflammation, thrombosis, and neointimal proliferation after endovascular stenting compared with the conventional stenting approach. A further hypothesis asserted was that the oil coating provided lubrication to the stent, thus decreasing the injury to the vascular wall.
The study went on to analyze the drug loading capacity of biological oil based stent coatings. Balloon mounted bare stents were dip-coated in a biological oil solution with the maximal solublizable amount of different drugs (a separate drug for each trial), and compared with polymer coated, drug loaded, stents. According to the release rate curves, there was a clear indication that drug release was fast in the first 24 hours with more than 20% of the drug released, for the oil based coatings. The release rate after the first 24 hours was much slower, and continued for a period up to about six weeks.
Another aspect of the study looked at the efficacy of drug loaded biological stents to decrease inflammation and neointimal hyperplasia in a porcine coronary stent model. In this part of the study, glue or modified glue (biological oil) coated stainless steel stents were loaded with different drugs. The result was that the characteristics of the particular drug loaded onto the stent were the major factor to the reduction of restenosis, and the biological oil did not have a major impact on either causing or reducing inflammation.
A further comment indicated that in the studies comparison was made between biological oil based drug loaded stents and bare stents to find differences in inflammation, injury, and hyperplasia. Inflammation, injury, and neointimal hyperplasia resulted in in-stent area stenosis. Any anti-inflammation observed was the result of the particular drug loaded on the stent, regardless of biological oil, or polymer, coating.
PCT Application Publication No. WO 03/039612 is directed to an intraluminal device with a coating containing a therapeutic agent. The publication describes coating an intraluminal device with a therapeutic agent comprised of a matrix that sticks to the intraluminal device. The matrix is formed of a bio-compatible oil or fat, and can further include alfa-tocopherol. The publication further indicates that an oil or fat adheres sufficiently strongly to the intraluminal device so that most of the coating remains on the intraluminal device when it is inserted in a body lumen. The publication further states that the oil or fat slows the release of the therapeutic agent, and also acts as an anti-inflammatory and a lubricant. The publication goes on to indicate that the oil or fat can be chemically modified, such as by the process of hydrogenation, to increase their melting point. Alternatively, synthetic oils could be manufactured as well. The oil or fat is further noted to contain fatty acids.
The '612 publication provides additional detail concerning the preferred oil or fat. It states that a lower melting point is preferable, and a melting point of 0° C. related to the oils utilized in experiments. The lower melting point provides a fat in the form of an oil rather than a wax or solid. It is further stated that oils at room temperature can be hydrogenated to provide a more stable coating and an increased melting point, or the oils can be mixed with a solvent such as ethanol. Preferences were discussed for the use of oils rather than waxes or solids, and the operations performed on the fat or oil as described can be detrimental to the therapeutic characteristics of some oils, especially polyunsaturated oils containing omega-3 fatty acids.
U.S. Publication No. 2003/0083740 similarly discusses the use of certain oils as a matrix for delivery of drugs. More specifically, this publication is directed to a method for forming liquid coatings for medical devices such as stents and angioplasty balloons. The liquid coatings can be made from biodegradable materials in liquid, low melting solid, or wax forms, which preferably degrade in the body without producing potentially harmful fragments. These fragments occur with harder coatings that fracture and break off after implantation. The liquid coatings may also contain biologically active components, such as drugs, which are released from the coatings through diffusion from the coatings and the degradation of the coatings.
Some of this second group of references do refer to the use of oils as a drug delivery platform. However, there is no realization of the difficulty of using an oil for the controlled release of a therapeutic agent in a long term application. There is further no indication that the coatings described in the above references are bio-absorbable, while also providing a controlled release of biologically active components, such as drugs. For controlled release of a drug, the above references require use of a polymer based coating either containing the drug or applied over the drug on the medical device.
What is desired is a bio-absorbable delivery agent having non-inflammatory characteristics that is able to be prepared in combination with at least one therapeutic agent for the delivery of that therapeutic agent to body tissue in a long term controlled release manner.